Synthetic small-molecule RNA ligands: future prospects as therapeutic agents

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.

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A Brief Introduction to Porphyrin Compounds Used in Tumor Imaging and Therapies

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520999201209212745 ◽

2020 ◽

Vol 20 ◽

Author(s):

Lili Pan ◽

Yu Ma ◽

Xiaoai Wu ◽

Huawei Cai ◽

Feng Qin ◽

...

Keyword(s):

Tumor Imaging ◽

Photoacoustic Imaging ◽

Therapeutic Agents ◽

Biochemical Properties ◽

Therapeutic Effects ◽

Future Prospects ◽

Animal Tissues ◽

Sonodynamic Therapy ◽

Porphyrin Derivatives ◽

Porphyrin Analogues

Abstract:: As a group of heterocyclic macrocycle organic natural compounds occurring universally in animal tissues and plants, porphyrins are composed of four modified pyrrole subunits. Porphyrin analogues/derivatives possess multiple biochemical properties because of their unique structures and have been extensively investigated in cancer treatment. Studies have shown that porphyrins and their derivatives have the ability to locate in tumor cells in a variety of human cancers, and these compounds not only exhibit potent therapeutic effects as photodynamic agents but also show promising properties in medicinal imaging, such as MRI, photoacoustic imaging, fluorescence imaging and PET/SPECT imaging. This paper reviews the recent reports of porphyrin derivatives as therapeutic agents used in tumor therapies, such as sonodynamic therapy, photodynamic therapy and radiotherapy, as well as imaging agents for multimodality tumor imaging. The limitations of porphyrin-based compounds in tumor treatments and future prospects are also summarized.

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Coumarin Hybrids: Promising Scaffolds in the Treatment of Breast Cancer

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190308122509 ◽

2019 ◽

Vol 19 (17) ◽

pp. 1443-1458 ◽

Cited By ~ 2

Author(s):

Rohit Bhatia ◽

Ravindra K. Rawal

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Therapeutic Agents ◽

Toxicity Profile ◽

Biological Targets ◽

Organ Systems ◽

Hybrid Molecules ◽

Cause Of Deaths ◽

Low Toxicity ◽

Diverse Mode

: Breast cancer is the most common invasive cancer in women, and the second main cause of deaths in women, after lung cancer. There is continuous advancement in the development of therapeutic agents against breast cancer in recent years and it is still in progress. Development of hybrid molecules by combining different pharmacophores to obtain significant biological activity is an excellent approach. Coupling of coumarin scaffold with other distinct motifs has led to the design of newer compounds against breast cancer. These distinct pharmacophores possess a diverse mode of action as well as selectivity. It has been reported in the literature that coumarin hybrids possess significant potency against breast cancer by binding to various biological targets which are associated with breast cancer. Due to low toxicity profile on various organ systems, coumarin hybrids have nowadays attracted the keen attention of researchers to explore their therapeutic ability against breast cancer. Reported coumarin hybrids include coupling with isoxazole, thiazole, monastrol, chalcone, triazole, sulphonamide, triphenylethylene, benzimidazole, pyran, imidazole, stilbene, oestrogen, phenylsulphonylfuroxan, etc. In the present review, a description of various coumarin hybrid molecules has been presented along with their structural-activity relationships.

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Development of a Novel High-Throughput Screen and Identification of Small-Molecule Inhibitors of the Gα–RGS17 Protein–Protein Interaction Using AlphaScreen

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057111410427 ◽

2011 ◽

Vol 16 (8) ◽

pp. 869-877 ◽

Cited By ~ 13

Author(s):

Duncan I. Mackie ◽

David L. Roman

Keyword(s):

Small Molecule ◽

High Throughput ◽

Protein Interaction ◽

High Throughput Screening ◽

Drug Targets ◽

Screening Method ◽

Fold Increase ◽

Rgs Proteins ◽

High Throughput Screen ◽

Protein Protein Interaction

In this study, the authors used AlphaScreen technology to develop a high-throughput screening method for interrogating small-molecule libraries for inhibitors of the Gαo–RGS17 interaction. RGS17 is implicated in the growth, proliferation, metastasis, and the migration of prostate and lung cancers. RGS17 is upregulated in lung and prostate tumors up to a 13-fold increase over patient-matched normal tissues. Studies show RGS17 knockdown inhibits colony formation and decreases tumorigenesis in nude mice. The screen in this study uses a measurement of the Gαo–RGS17 protein–protein interaction, with an excellent Z score exceeding 0.73, a signal-to-noise ratio >70, and a screening time of 1100 compounds per hour. The authors screened the NCI Diversity Set II and determined 35 initial hits, of which 16 were confirmed after screening against controls. The 16 compounds exhibited IC50 <10 µM in dose–response experiments. Four exhibited IC50 values <6 µM while inhibiting the Gαo–RGS17 interaction >50% when compared to a biotinylated glutathione-S-transferase control. This report describes the first high-throughput screen for RGS17 inhibitors, as well as a novel paradigm adaptable to many other RGS proteins, which are emerging as attractive drug targets for modulating G-protein-coupled receptor signaling.

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Biosynthesis of Nature-Inspired Unnatural Cannabinoids

Molecules ◽

10.3390/molecules26102914 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2914

Author(s):

Kevin J. H. Lim ◽

Yan Ping Lim ◽

Yossa D. Hartono ◽

Maybelle K. Go ◽

Hao Fan ◽

...

Keyword(s):

Synthetic Biology ◽

Cannabis Sativa ◽

Genetic Manipulation ◽

Therapeutic Agents ◽

Orphan Receptors ◽

Complex Chemical ◽

Biological Targets ◽

Chemical Structures ◽

Commercial Use ◽

Wide Range

Natural products make up a large proportion of medicine available today. Cannabinoids from the plant Cannabis sativa is one unique class of meroterpenoids that have shown a wide range of bioactivities and recently seen significant developments in their status as therapeutic agents for various indications. Their complex chemical structures make it difficult to chemically synthesize them in efficient yields. Synthetic biology has presented a solution to this through metabolic engineering in heterologous hosts. Through genetic manipulation, rare phytocannabinoids that are produced in low yields in the plant can now be synthesized in larger quantities for therapeutic and commercial use. Additionally, an exciting avenue of exploring new chemical spaces is made available as novel derivatized compounds can be produced and investigated for their bioactivities. In this review, we summarized the biosynthetic pathways of phytocannabinoids and synthetic biology efforts in producing them in heterologous hosts. Detailed mechanistic insights are discussed in each part of the pathway in order to explore strategies for creating novel cannabinoids. Lastly, we discussed studies conducted on biological targets such as CB1, CB2 and orphan receptors along with their affinities to these cannabinoid ligands with a view to inform upstream diversification efforts.

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Application of Cryo-Electron Microscopy on Drug Discovery

Microscopy and Microanalysis ◽

10.1017/s143192762101120x ◽

2021 ◽

Vol 27 (S1) ◽

pp. 3250-3250

Author(s):

Viswanath Vittaladevaram ◽

Kranthi Kuruti

Keyword(s):

Electron Microscopy ◽

Protein Complexes ◽

Lead Discovery ◽

Biologically Relevant ◽

Biological Targets ◽

3 Dimensional ◽

Drug Molecules ◽

Cryo Electron Microscopy ◽

Therapeutic Molecules ◽

Novel Drug

AbstractThe key aspect for development of novel drug molecules is to perform structural determination of target molecule associated with its ligand. One such tool that provides insights towards structure of molecule is Cryo-electron microscopy which covers biological targets that are intractable. Examination of proteins can be carried out in native state, as the samples are frozen at -175 degree Celsius i.e. cryogenic temperatures. In addition to this, there were no limits for molecular and functional structures of proteins that can be imagined in 3-dimensional form. This includes ligands which unravel mechanisms that are biologically relevant. This will enable to better understand the mechanisms that are used for development of new therapeutics. Application of Cryo-electron microscopy is not limited to protein complexes and is considered as non-specific. Intervention of Cryo-EM would allow to analyse the structures and also able to dissect the interaction with therapeutic molecules. The study determines the usage of cryo-EM for providing resolutions that are acceptable for lead discovery. It also provides support for lead optimization and also for discovery of vaccines and therapeutics.

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Advance investigation on synthetic small-molecule inhibitors targeting PD-1/PD-L1 signaling pathway

Life Sciences ◽

10.1016/j.lfs.2021.119813 ◽

2021 ◽

pp. 119813

Author(s):

Annoor Awadasseid ◽

Yanling Wu ◽

Wen Zhang

Keyword(s):

Signaling Pathway ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Synthetic Small Molecule

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Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

Diversity Oriented Synthesis ◽

10.2478/dos-2013-0001 ◽

2013 ◽

Vol 1 (1) ◽

Cited By ~ 5

Author(s):

Warren R.J.D. Galloway ◽

David R. Spring

Keyword(s):

Small Molecule ◽

Structural Diversity ◽

Library Size ◽

Diversity Oriented Synthesis ◽

Biological Targets ◽

Small Molecule Screening ◽

Chemistry Research ◽

Large Numbers ◽

Small Molecule Libraries ◽

Scaffold Diversity

AbstractMedicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

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